Vinyl chloroformate (VOC-C1) has been introduced by this laboratory as a highly effective reagent for the protection of amino and hydroxyl groups and for the selective N-dealkylation of tertiary amines. A major objective of the proposed research is the further development of the VOC moiety as a preparative tool, especialy in the area of peptide synthesis. To reach this goal, new reagents for the transfer of the VOC unit and, more important, of substituted enyloxycarbonyl species to nucleophiles are required along with general methodology for the formation of substituted enol derivatives including enol carbamates, carbonates, and haloformates. Recent advances include the first general route to enol chloroformates, two useful new syntheses of enol carbamates and carbonates including a catalytic process which is both regiospecific and stereospecific, an efficient preparation of fluoroformates, and a general preparation of enyloxy arylthio carbonates for conversion to substituted VOC peptides. VOC N-dealkylation has also been applied to the formation of the analgesic, nalbuphine, from oxycodone in 71% overall yield. Other goals in peptide chemistry include the design and development of better methods of "racemization free" peptide bond formation based on the reactions of "hot" reagents with peptide acids to directly produce under mild conditions "cool", weakly activated peptide ester acylating agents. Other methodology developed under this grant includes new routes to isoxazoles and other synthetically and pharmaceutically useful heteroaromatic systems.